A Class Above:
Dr. Angela Brodie Wins the 2005 Kettering Prize

Dr. Brodie is the first woman to receive this international honor.

Dr. Brodie in her lab at Maryland
Dr. Brodie in her lab at Maryland

Dr. Angela Brodie has never much feared heights. The child of two mountaineers and a skilled rock climber herself, Brodie’s life work illustrates the rewards of a steady hike. Now an editor of the leading journal Cancer Research, Brodie recalls their rejection of her first paper, which reported the laboratory success of aromatase inhibitors at reducing estrogen levels. “They thought the finding was too obvious,” says Brodie. After all, aromatase was known to be a key enzyme in estrogen biosynthesis. Decades later, thanks to Brodie’s persistence, aromatase inhibitors have become a first-line therapy for estrogen-sensitive breast cancers, extending the lives of thousands of post-menopausal women around the world. This year her achievements have been recognized with one of the scientific community’s highest honors: the Charles F. Kettering Prize, given for the most outstanding recent contribution to the diagnosis or treatment of cancer. Dr. Brodie is the first woman to receive this international honor.

Born in Manchester, England, in 1934, Angela Brodie grew up in a home saturated with science and determination. Her mother’s family climbed mountains. In a way, Brodie owes her life to that sport, for her mother’s brother introduced two of his rock-climbing buddies to two of his sisters, resulting in two marriages. Brodie describes her mother as a well-mannered, well-read, and very bright homemaker, who also understood the importance of a good foothold. She taught her two children “not to let other people get ahead of you.” Brodie’s brother, eight years her junior, is now a psychologist in Perth, Australia.

It was her father, however, who filled the house with the language of science. An organic chemist specializing in polyurethanes, Herbert Hartley inspired his daughter’s broad-ranging love of scientific pursuit. “He was always talking to me about science,” recalls Brodie with pleasure, “always interesting me in it.”

As a child, Brodie attended a Quaker boarding school for nine years. After earning her undergraduate degree in biochemistry from the University of Sheffield, she took a job in a blood bank, running routine assays on Rh-factor while hoping to find more interesting work in medical research. Fortuitously for her and for today’s breast-cancer patients, it was her father’s mountaineering friend, biochemist Raymond Clayton, who had a laboratory position available for her at the Christie Cancer Hospital, Manchester, U.K. There she worked for two years on estrogen-dependent breast cancer before leaving to pursue her doctorate in chemical pathology at the University of Manchester.

“At that time, nobody knew about estrogen receptors. The standard treatment was ovariectomy, adrenalectomy, and hypophysectomy [ablation of the pituitary gland],” says Brodie. “It seemed like there had to be a better way.” Others at the Christie Hospital pursued similar thinking. In fact it was a close colleague there, oncologist Moira Cole, who later went on to conduct the first clinical trials of tamoxifen, an agent that blocks the estrogen-receptors found on hormone-sensitive tumors.

Work at the Christie Hospital continued to influence Brodie even after her doctoral research immersed her in the study of a different hormone, aldosterone, and led her to NIH-sponsored fellowship training at the renowned Worcester Foundation for Experimental Biology in Shrewsbury, Massachusetts. There, steroid researchers had developed oral contraceptives and were working on methods of in-vitro fertilization. When Brodie arrived, scientists were focused on estrogen biosynthesis as it related to the birth control pill.

At age 16 in the Swiss Alps
At age 16 in the Swiss Alps

Two of these researchers held particular importance for Angela Brodie. Organic chemist Harry Brodie would soon become her husband. Later, his laboratory partner, Dr. Mika Hayano, would herself develop breast cancer, undergo standard treatment, and die in her mid-forties. Meanwhile Angela Brodie had shifted away from aldosterone research, taking a year off to have her first child, then returning to laboratory work part-time in her husband’s lab, where they focused on aromatase, a key enzyme in the body’s production of estrogen. Soon they had a second son.

Despite her husband’s primary interest in the work’s application to contraception, Brodie became further determined to find a clinically useful link between the nature of estrogen biosynthesis and the needs of breast-cancer patients like Mika. However she lacked the confidence to apply for a grant. Molecular biologist Joy Hochstadt worked her over. As Brodie recalls, “We had an ardent feminist at Worcester. There weren’t too many. She asked me why I didn’t put in a grant application. I said, ‘Well, I’m only working part time . . .’ and she said, ‘So? Almost everyone is only working part time!’ She spurred me into action. She really encouraged me, and the first application was funded.”

Angela Brodie continued research at the Worcester Foundation for eighteen years, developing aromatase inhibitors and showing their clinical efficacy in model systems. Harry Brodie took a different path, leaving laboratory research in 1978 and becoming an administrator at the NIH.

It was eagerness to initiate clinical trials of aromatase inhibitors that brought Angela Brodie to the University of Maryland in 1979. “I was really keen to do clinical trials with the compound, because we all saw that it worked better than tamoxifen in the model systems,” she says. With the special encouragement of Maryland reproductive endocrinologist Cornelia Channing, she came south with high hopes of launching trials. Two disappointments awaited. Not only did the cancer center temporarily lack a director and therefore the readiness to take on the trials at that point in time, but on the very day that Brodie arrived on campus, she discovered that Dr. Channing was herself undergoing mastectomy for breast cancer.

A little over a year later, Brodie presented a paper at a conference in Rome, describing her research on aromatase inhibitors. A British oncologist named Charles Coombes approached afterwards, asking, “What would it take to get this into the clinic?” From there a collaboration was born. Synthesizing a kilogram of aromatase inhibitors in her Baltimore laboratory, Brodie shipped them across the sea in small batches to the Royal Marsden Hospital in London, where Coombes delivered the experimental medicine to eleven women with advanced breast cancer. Four of these initial women demonstrated immediate and dramatic benefit. Their tumors shrank to less than 50% of their original sizes. A fifth patient saw her tumor stabilize. “We had a photograph of one woman whose tumor had eroded her rib—awful, awful—but after five months on the aromatase inhibitor, the bone had healed,” recalls Brodie. “Prior to that, it had been very difficult to interest pharmaceutical companies in taking the compound further, but once they’d seen clinical data, we were able to interest Ciba-Geigy [now Novartis] in expanding the trials and taking on the compound.”

In Rockville, Maryland, medical oncologist Kenneth Miller, MD, specializes in the care of women with breast cancer. He calls aromatase inhibitors “a quantum leap in hormonal therapy, useful for preventing recurrence and for reducing the risk of cancer in the other breast.” His patients also appreciate the medicines. Says Jill Campiglia, who experienced unpleasant side effects during her three years on tamoxifen, “I’ve been on aromatase inhibitors for two years, and I can tell you that I’m in great health. I’ve never had any side effects.”

Dr. Brodie in the mountains of British Columbia with son
Dr. Brodie in the mountains of British Columbia
with son John

Sitting in her spacious, sunny office in Health Sciences Facility I, Brodie expresses humble satisfaction that her life’s work has made such an impact. For thirty years, steadily supported by NIH research grants, she has pursued the clinical benefit of aromatase inhibitors. Her eldest son, Mark Brodie, recalls family vacations taking place “wherever the aromatase conferences were being held that year.” A school teacher in Los Angeles, he describes his mother as being “low key and understated about everything, especially about herself. She sent me an e-mail that she had won a prize, and it was only when I went to the website link that I realized what a big deal it was.”

News of the illustrious Kettering Prize had surprised Brodie. She didn’t even know she had been nominated. “After the award was announced, I heard from people all over the place, people I hadn’t heard from in years,” she says, smiling. “I guess I was surprised because I thought that nobody was noticing the aromatase inhibitors. They’d been coming along for so long.”
With others, Gauri Sabnis, PhD, is now conducting post-doctoral research in Brodie’s lab, exploring potential mechanisms by which cancer cells might eventually develop resistance to aromatase inhibitors. “Everybody is happy about the award,” says Sabnis. “People already knew about Dr. Brodie, but after the award was announced, everybody was approaching us saying, ‘Oh, you work with Dr. Brodie! You’re almost famous!’” Sabnis joined Brodie’s lab in 2002, and her joy at her mentor’s success is palpable.

“The lab is like one big family,” she explains. “Dr. Brodie is really amazing. She is flexible; she is supportive. She never insists that we have to be in the lab at eight o’clock every morning. She understands that we have exams, and she allows us to study for them. She brings chocolates and cookies to lab meetings. She always has time for her students and her post-docs. To talk about Dr. Brodie, you could go on for a long time.”

Senior colleagues agree. Associate professor of pharmacology Dr. Vincent Njar began collaborating with Brodie in 1996, and he speaks of her with both esteem and friendship. “Dr. Brodie is very honest. She has high integrity.” Looking back over their decade of shared research, he describes Brodie as a moderating voice in the laboratory group. “When we get results from our work, sometimes of course we become overly excited, but she will always insist that we repeat the experiments, to make sure that what we are looking at is really true. We do not just rush on with the first set of results that we get. That’s an excellent way to deal with the nature of science. She is very thorough. She is very energetic. She loves her job.” Assistant dean and asso-ciate professor of pharmacology Jordon Warnick, PhD, summarizes, “Dr. Brodie is absolutely wonderful. I can’t think of anyone she doesn’t work well with.”

And she is almost always working. On the editorial boards of four professional journals and a regular reviewer of grant applications to the NIH and the U.S. Department of Defense, Brodie’s pleasure reading has narrowed to the New Yorker. “Novels are out, unfortunately,” she says, though she still reserves time each week for gardening, and for riding her Morgan horse.

Receiving the Kettering Prize from GM CEO Richard Wagoner, Samuel A. Wells Jr., MD, Duke professor of surgery and president of the GM Cancer Research Awards, and Phillip A. Sharp, PhD, of MIT
Receiving the Kettering Prize from GM CEO Richard Wagoner, Samuel A. Wells Jr., MD, Duke professor of surgery and president of the GM Cancer Research Awards, and Phillip A. Sharp, PhD, of MIT

Research takes precedence. Currently Brodie is investigating metastatic breast cancer and mechanisms by which tumor cells can evade treatment. She is also studying inhibitors of androgen synthesis, with hopes for clinical benefit in men with prostate cancer. One of these studies is nearing the stage of clinical trials.

Mark Brodie understands his mother’s purpose. “My mom always used to say that no matter what your occupation is, no matter what you’re doing, you should be contributing to society in some way. When I was an actor, she would say, ‘There are good movies and bad movies, good television shows and bad television shows. Work on the ones that will have a positive impact.’”

In addition to the Kettering Prize, the annual General Motors Cancer Research Awards include the Alfred P. Sloan Prize, given for the most outstanding recent contribution in basic science related to cancer research; and the Charles P. Mott Prize, given for the most outstanding recent contribution related to the cause or prevention of cancer. Each award brings a medal and $250,000. Brodie has taped Governor Ehrlich’s letter of congratulations to her office door. “I even got a certificate from the Maryland State Assembly,” she says. “I’ve had a lot of messages from people all over the campus who have heard about it. The support has been wonderful.”

What are Aromatase Inhibitors?

Aromatase is an enzyme necessary for the synthesis of estrogen, a naturally occurring hormone that serves as a growth factor to approximately 70% of breast cancers. After menopause, when the ovaries stop making estrogen, other tissues, such as fat (including the breast itself) become the body’s primary source of estrogen. As cancer-fighting agents, aromatase inhibitors work by reducing the amount of estrogen produced by the adrenal glands. The medicines act by starving hormone-dependent cancers of their estrogen fuel supply.

A sister class of drugs called “selective estrogen-receptor modulators,” or “SERMS,” bind to estrogen receptors in hormone-dependent cancer cells, acting as physical barriers to the binding of estrogen itself. However, these drugs—which include tamoxifen (Nolvadex), raloxifene (Evista), and toremifene (Fareston)—act as mild agonists at the receptor site, producing unwanted estrogenic side effects such as an increased risk of stroke and a higher incidence of vaginal bleeding, endometrial hyperplasia, and endometrial cancer.

Aromatase inhibitors steer clear of these side effects. As a class, these compounds are better tolerated by women, with the most likely side effect being potential loss of bone mineral density. Repeated studies have shown that aromatase inhibitors delay the progression of advanced, hormone-sensitive breast cancer for longer periods of time than does tamoxifen.

Currently three different aromatase inhibitors are approved by the Food and Drug Administration: anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin). Each is a once-a-day pill, prescribed to post-menopausal women with advanced disease. Tamoxifen is still the first line treatment for early breast cancer, but recent studies suggest that aromatase inhibitors may be better than tamoxifen earlier in disease progression, or even in breast cancer prevention.

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